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A kind of method for preparing apabetalone, intermediate and preparation method of intermediate thereof
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An intermediate and solid technology, applied in the field of preparing hypolipidemic drug Apabetalone, can solve the problems of increasing reaction steps, low overall yield and the like, and achieves the effects of fewer reaction steps, improved overall yield, and reduced cost
Active Publication Date: 2021-07-27
SHANGHAI UNIV OF ENG SCI
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[0011] This route introduces protecting groups, increases the reaction steps, and uses catalyst ligands in the ring-forming process, and the overall yield is low
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Embodiment 1
[0061] Example 1 Preparation of 2-bromo-4,6-dimethoxybenzaldehyde (1)
[0062] Take 3,5-dimethoxybromobenzene (20g, 90mmol) and add it to a 250mL there-necked flask, add N,N-dimethylformamide (33.6g, 459.7mmol), stir at 0°C, then dropwise add trichloromethane Phosphorus oxide (16.88 g, 108 mmol) was dripped, and the reaction was stirred at room temperature for 30 min, and then heated to 100° C. for 4 h. After the reaction was completed, the reaction solution was poured into 100 mL of crushed ice, left standing at 25°C for 12 h, filtered, and the filter cake was washed with petroleum ether to obtain 19.7 g of 2-bromo-4,6-dimethoxybenzaldehyde with a yield of 19.7 g. 87.2%.
[0063] 1 H NMR(400MHz, CDCl3)δ10.33(s,1H),6.80(d,J=2.2Hz,1H),6.45(d,J=2.2Hz,1H),3.91(s,3H),3.89(s , 3H).
Embodiment 2
[0064] Example 2 Preparation of 2-bromo-4,6-dimethoxybenzaldehyde (2)
[0065] Take 3,5-dimethoxybromobenzene (20g, 90mmol) and add it to a 250mL there-necked flask, add N,N-dimethylformamide (33.6g, 459.7mmol), stir at 0°C, then dropwise add trichloromethane Phosphorus oxide (16.88 g, 108 mmol) was dripped, and the reaction was stirred at room temperature for 30 min, and then heated to 80° C. for 6 h. After the reaction was completed, the reaction solution was poured into 100 mL of crushed ice, left standing at 25°C for 12 h, filtered, and the filter cake was washed with petroleum ether to obtain 16.8 g of 2-bromo-4,6-dimethoxybenzaldehyde with a yield of 16.8 g. 74.4%.
[0066] The spectral detection results were the same as those in Example 1.
Embodiment 3
[0067] Example 3 Preparation of 2-bromo-4,6-dimethoxybenzoic acid (1)
[0068] Take 2-bromo-4,6-dimethoxybenzaldehyde (5g, 20.4mmol) and add it to a 250mL reaction flask, then add tetrahydrofuran (50mL), stir to dissolve, then add sulfamic acid (6.93g, 71.4mmol, 3.5eq) Stir to dissolve. Weigh sodium chlorite (6.46 g, 71.4 mmol) and dissolve it in water (25 mL), drop the solution into a reaction flask, and react at 25° C. for 1 h. Ethyl acetate was added for extraction (75 mL×2), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (75 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain 4.3 g of 2-bromo-4,6-dimethoxybenzoic acid with a yield of 80.4%.
[0069] 1 H NMR(400MHz, DMSO)δ13.08(s,1H),6.79(d,J=2.1Hz,1H),6.65(d,J=2.1Hz,1H),3.81(s,3H),3.79(s , 3H).
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Abstract
The present invention provides a kind of preparation method of Apabetalone, comprises the steps: the first intermediate 2-bromo-4,6-dimethoxybenzoic acid and the second intermediate 4-(2-hydroxyethoxy)-3 , 5-dimethylbenzamidine hydrochloride reacts under the action of a catalyst in an alkali-containing organic solvent to obtain Apabetalone. The total yield of the invention is above 33.4%, the raw materials are easy to obtain, the process is simple, the reaction conditions are mild, the aftertreatment method is simple, the yield of each step and the total yield are high, and the cost can be reduced. Apabetalone is a drug for the treatment of cardiovascular diseases such as atherosclerosis, and has a good application prospect. The present invention also provides intermediate 4-(2-hydroxyethoxy)-3,5-dimethylbenzamidine hydrochloride and its preparation method and compound 2-bromo-4,6-dimethoxy compound for the synthesis of Apabetalone The preparation method of benzoic acid.
Description
technical field [0001] The invention relates to the technical field of organic synthesis and preparation of raw materials, in particular to a method for preparing a hypolipidemic drug Apabetalone (RVX-208), an intermediate and a preparation method of the intermediate. Background technique [0002] Apabetalone (RVX-208), chemical name: 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxyquinazoline-4(3H )-ketone, with chemical formula such as formula I, developed by Resverlogix Company, is mainly used to treat cardiovascular diseases such as atherosclerosis, and is currently undergoing phase III clinical research. [0003] Apabetalone (RVX-208) is a BET bromodomain inhibitor that selectively acts on the BD2 bromodomain. In-depth study of this drug will help to clarify the physiological roles of the BD1 and BD2 bromodomains of the BET bromodomain. Apabetalone (RVX-208) also has HIV latent activation effect, which is of great significance to HIV cure research. [0004] ...
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